A number of human malignant and non-malignant diseases have as one of their distinguishing features the hyperproliferation of cells. In these diseases, cells proliferate at abnormally high rates. The cells found in cancerous tumors and leukemias grow and divide uncontrollably, which accounts in part for their rapid spread in the body. Similarly, with some non-malignant diseases such as psoriasis, the cells also grow and divide at abnormally high rates. In these diseases, the hyperproliferating cells are present in a relatively undifferentiated state. Undifferentiated cells are able to grow and divide. Once a cell differentiates, however, it loses the ability to proliferate. Some proposed treatments have been aimed towards inducing cell differentiation to stop cell proliferation, and thus bring the diseases under control.
Recently it has been found that sphingolipids play important roles in cell growth, oncogenesis, and differentiation (Hannun, Y. A. and Bell, R. M. (1989) Science 243: 500-507). At least 300 different sphingolipids are synthesized in various mammalian cell types. Structurally, sphingolipids are composed of a long-chain sphingoid base, an amide-linked fatty acid, and a polar head group at the 1-position. Except for ceramide, which has hydroxyl at the 1-position, and for sphingolmyelin, which has a phosphorylcholine head group, all other sphingolipids contain carbohydrate head groups and hence are designated glycosphingolipids. Sphingolipid breakdown products are emerging as a novel class of cell regulatory molecules. Sphingolipid breakdown products, sphingosine and ysosphingolipids, inhibit protein kinase C, believed to be a pivotal enzyme in cell regulation and signal transduction (Hannun, Y. A. et al. (1986) J. Biol Chem. 261: 12604-12609). Sphingolipids and lyso-sphingolipids affect significant cellular responses and exhibit anti-tumor promoter activities in various mammalian cells (Hannun, Y. A. and Bell, R. M. (1987) Science 235: 670-674; Hannun, Y. A. et al. (1987) J. Biol. Chem. 262: 13620-13626; and Wilson, E. St al. (1987) Arch. Biochem. Biophys. 259: 204-214).
U.S. Pat. No. 4,816,450 issued Mar. 28, 1989 to Bell discloses long chain bases, generally sphingosine and sphingosine derivatives, useful for inhibiting protein kinase C. Activation of protein kinase C has been identified as fundamental to tumor promotion, cellular transformation and to understanding the inhibition by anti-tumor agents.
It has also been found that ceramide and cell-permeable ceramides with shorter N-acyl chains are potent regulators of cell differentiation as disclosed in co-pending application Ser. No. 566,978 filed Aug. 13, 1990 and in Okazaki et al. (1990) J. Biol. Chem. 285: 15823-1583. Exposure of cells to exogenously applied ceramide and such derivatives induces cell differentiation.
Interferon which induces cell differentiation has been tested for treatment of tumors. Similarly, vitamin D.sub.3 which induces differentiation of HL-60 cells, a human myelocytic leukemia cell line, has also been tested for tumor treatment.
Despite efforts in developing treatments for diseases characterized by cellular hyperproliferation, there is still a need for treatments for these diseases.
Accordingly, it is an object of the invention to provide methods and compositions for inducing cell differentiation and/or inhibition of cell growth. It is a further object to provide methods and pharmaceutical compositions for treating diseases characterized by hyperproliferation of cells. Other objects of the present invention will become apparent from a review of the specification and appended claims.